The main objective of this proposal is to investigate neurotoxicities caused by translational protein complex aggregation after brain ischemia. An episode of brain ischemia leads to delayed neuronal death at 72 hours of reperfusion. We have recently found that brain ischemia causes aggregation of translational complex, i.e., ribosomes and ribosome-associated proteins, thus demolishing protein synthesis machinery in ischemic vulnerable neurons. 4 lines of evidence strongly suggest that destruction of protein synthesis machinery by aggregation plays a causative role in delayed neuronal death after brain ischemia: (1) Translational complex aggregation is seen as early as 2 hours, and is progressively accumulated in neurons until their death at about 72 hours of reperfusion; (2) Translational complex aggregation occurs only in brain regions where neurons are destined to die, but does not take place in brain areas where neurons survive the same ischemic insult, suggesting that translational complex aggregation may not be an epiphenomenon; (3) All measures that prevent translational complex aggregation enhance resistance of neurons to ischemia; (4) Protein synthesis is irreversibly destroyed by translational complex aggregation in vulnerable neurons after ischemia. Based on these observations, we propose a new hypothesis for delayed neuronal death after ischemia whereby the ischemia-induced cascade of energy failure, disabilities of protein chaperoning and protein degradation cumulatively cause translational complex aggregation, thus destroying protein synthesis machinery. Such destruction of protein synthesis machinery accumulates over time, and ultimately leads to delayed neuronal death after brain ischemia. Can translational complex aggregation be prevented? The answer should be positive, provided that the molecular mechanisms are understood. The objective of this proposal is to study molecular mechanisms of translational complex aggregation after brain ischemia.